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1.
Toxicol Pathol ; 42(2): 422-34, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-23651588

RESUMEN

Dexamethasone was given in 2 oral dosing regimens with repeat dose oral administration of the gamma secretase inhibitor (GSI), PF-03084014, in Sprague-Dawley (SD) rats in order to evaluate the effects of coadministration of dexamethasone on GSI-induced goblet cell hyperplasia (GCH) in the intestinal tract. Safety end points were evaluated in 1 week and 1 month studies. The dosing regimens tested in the 1-month studies included a 1-week pretreatment with 1.0 mg/kg dexamethasone followed by a 3-week repeat dose treatment with 100 mg/kg GSI or concurrent intermittent treatment with 1.0 mg/kg dexamethasone on weeks 1 and 3 and repeat dose treatment with 100 mg/kg GSI for 4 weeks. Pretreatment with dexamethasone for 1 week transiently mitigated the severity of intestinal GCH for up to 1 week. Intermittent coadministration of dexamethasone on weeks 1 and 3 with GSI repeat dosing for 4 weeks mitigated intestinal GCH for up to 4 weeks post treatment. Treatment-related morbidity and mortality occurred on day 7 with 150 mg/kg GSI and 5 mg/kg dexamethasone coadministration, and on days 13, 14, and 23 with 100 mg/kg GSI and 1 mg/kg dexamethasone coadministration.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Dexametasona/administración & dosificación , Células Caliciformes/efectos de los fármacos , Hiperplasia/patología , Tetrahidronaftalenos/administración & dosificación , Valina/análogos & derivados , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Dexametasona/sangre , Dexametasona/toxicidad , Células Caliciformes/citología , Células Caliciformes/metabolismo , Intestinos/citología , Intestinos/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/toxicidad , Valina/administración & dosificación , Valina/sangre , Valina/toxicidad
2.
Bioorg Med Chem Lett ; 23(8): 2344-8, 2013 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-23489629

RESUMEN

N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11ß-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11ß-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Aminopiridinas/farmacocinética , Sulfonamidas/farmacocinética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Aminopiridinas/química , Aminopiridinas/farmacología , Glutatión/farmacocinética , Células HEK293 , Humanos , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología
3.
BMC Genomics ; 13: 355, 2012 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-22849360

RESUMEN

BACKGROUND: The androgen receptor plays a critical role throughout the progression of prostate cancer and is an important drug target for this disease. While chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq) is becoming an essential tool for studying transcription and chromatin modification factors, it has rarely been employed in the context of drug discovery. RESULTS: Here we report changes in the genome-wide AR binding landscape due to dose-dependent inhibition by drug-like small molecules using ChIP-Seq. Integration of sequence analysis, transcriptome profiling, cell viability assays and xenograft tumor growth inhibition studies enabled us to establish a direct cistrome-activity relationship for two novel potent AR antagonists. By selectively occupying the strongest binding sites, AR signaling remains active even when androgen levels are low, as is characteristic of first-line androgen ablation therapy. Coupled cistrome and transcriptome profiling upon small molecule antagonism led to the identification of a core set of AR direct effector genes that are most likely to mediate the activities of targeted agents: unbiased pathway mapping revealed that AR is a key modulator of steroid metabolism by forming a tightly controlled feedback loop with other nuclear receptor family members and this oncogenic effect can be relieved by antagonist treatment. Furthermore, we found that AR also has an extensive role in negative gene regulation, with estrogen (related) receptor likely mediating its function as a transcriptional repressor. CONCLUSIONS: Our study provides a global and dynamic view of AR's regulatory program upon antagonism, which may serve as a molecular basis for deciphering and developing AR therapeutics.


Asunto(s)
Antagonistas de Receptores Androgénicos/metabolismo , Receptores Androgénicos/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo , Antagonistas de Receptores Androgénicos/uso terapéutico , Antagonistas de Receptores Androgénicos/toxicidad , Animales , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inmunoprecipitación de Cromatina , Mapeo Cromosómico , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratones , Ratones SCID , Neoplasias de la Próstata/tratamiento farmacológico , Unión Proteica , Receptores Androgénicos/química , Receptores Androgénicos/genética , Análisis de Secuencia de ADN , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Bibliotecas de Moléculas Pequeñas/toxicidad , Trasplante Heterólogo
4.
Bioorg Med Chem Lett ; 22(2): 1230-6, 2012 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-22197140

RESUMEN

High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.


Asunto(s)
Descubrimiento de Drogas , Lactamas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/química , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Humanos , Lactamas/síntesis química , Lactamas/química , Masculino , Modelos Moleculares , Estructura Molecular , Neoplasias de la Próstata/cirugía , Receptores Androgénicos/metabolismo , Estereoisomerismo , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 20(9): 2897-902, 2010 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-20363126

RESUMEN

The design and development of a series of highly selective pyrrolidine carboxamide 11beta-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11beta-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11beta-HSD1 selective inhibitor 42.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Amidas/química , Inhibidores Enzimáticos/química , Hipoglucemiantes/química , Pirrolidinas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/síntesis química , Adamantano/química , Adamantano/farmacología , Amidas/síntesis química , Amidas/farmacología , Animales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cobayas , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Relación Estructura-Actividad
6.
J Clin Pharmacol ; 49(5): 513-33, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19299532

RESUMEN

Quantitative prediction of human pharmacokinetics is critical in assessing the viability of drug candidates and in determining first-in-human dosing. Numerous prediction methodologies, incorporating both in vitro and preclinical in vivo data, have been developed in recent years, each with advantages and disadvantages. However, the lack of a comprehensive data set, both preclinical and clinical, has limited efforts to evaluate the optimal strategy (or strategies) that results in quantitative predictions of human pharmacokinetics. To address this issue, the authors conducted a retrospective analysis using 50 proprietary compounds for which in vitro, preclinical pharmacokinetic data and oral single-dose human pharmacokinetic data were available. Five predictive strategies, involving either allometry or use of unbound intrinsic clearance from microsomes or hepatocytes, were then compared for their ability to predict human oral clearance, half-life through predictions of systemic clearance, volume of distribution, and bioavailability. Use of a single-species scaling approach with rat, dog, or monkey was as accurate as or more accurate than using multiple-species allometry. For those compounds cleared almost exclusively by P450-mediated pathways, scaling from human liver microsomes was as predictive as single-species scaling of clearance based on data from rat, dog, or monkey. These data suggest that use of predictive methods involving either single-species in vivo data or in vitro human liver microsomes can quantitatively predict human in vivo pharmacokinetics and suggest the possibility of streamlining the predictive methodology through use of a single species or use only of human in vitro microsomal preparations.


Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Modelos Biológicos , Farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Biometría , Semivida , Hepatocitos/metabolismo , Humanos , Tasa de Depuración Metabólica , Microsomas Hepáticos/metabolismo , Reproducibilidad de los Resultados , Estudios Retrospectivos , Especificidad de la Especie , Xenobióticos/farmacocinética
7.
Bioorg Med Chem Lett ; 19(13): 3493-7, 2009 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-19473839

RESUMEN

N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Aminopiridinas/síntesis química , Inhibidores Enzimáticos/síntesis química , Sulfonamidas/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animales , Línea Celular , Simulación por Computador , Cricetinae , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética
8.
J Pharmacol Exp Ther ; 324(1): 299-305, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17921190

RESUMEN

Glucocorticoids, through activation of the glucocorticoid receptor (GR), regulate hepatic gluconeogenesis. Elevated hepatic expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) play a key role in ligand-induced activation of the GR through the production of cortisol. Evidence from genetically modified mice suggests that inhibition of 11betaHSD1 might be a therapeutic approach to treat the metabolic syndrome. We have identified a potent 11betaHSD1 inhibitor, 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide (PF-915275), that is selective for the primate and human enzymes. The objective of this study was to demonstrate target inhibition with PF-915275 and to quantify the relationship between target inhibition and drug exposure in monkeys. We characterized the ability of PF-915275 to inhibit the conversion of prednisone, a synthetic cortisone analog that can be distinguished from the endogenous substrate cortisone, enabling a direct measure of substrate to product conversion without the complication of feedback. Adult cynomolgus monkeys were administered either vehicle or various doses of PF-915275 followed by a 10-mg/kg dose of prednisone. Prednisone conversion to prednisolone and the concentrations of PF-915275 were measured by liquid chromatography/tandem mass spectrometry. PF-915275 dose-dependently inhibited 11betaHSD1-mediated conversion of prednisone to prednisolone, with a maximum of 87% inhibition at a 3-mg/kg dose. An exposure-response relationship was demonstrated, with an estimated EC(50) of 391 nM (total) and 17 nM (free). Insulin levels were also reduced in a dose-related manner. These results should enable the development of a biomarker for evaluating target modulation in humans that will aid in identifying 11betaHSD1 inhibitors to treat diabetes and other related metabolic diseases.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Aminopiridinas/farmacocinética , Prednisona/sangre , Sulfonamidas/farmacocinética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Aminopiridinas/sangre , Aminopiridinas/farmacología , Animales , Biomarcadores/sangre , Línea Celular , Células Cultivadas , Cortisona/sangre , Cortisona/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hidrocortisona/sangre , Hidrocortisona/metabolismo , Insulina/sangre , Macaca fascicularis , Masculino , Prednisolona/sangre , Proteínas Serina-Treonina Quinasas/genética , Sulfonamidas/sangre , Sulfonamidas/farmacología , Transfección
9.
Clin Pharmacokinet ; 42(11): 969-84, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12908853

RESUMEN

The objective of this review is to evaluate the risks associated with the discovery and development of cytochrome p450 (CYP) 3A substrates. CYP3A is the most abundant p450 enzyme in human liver and is highly expressed in the intestinal tract. The enzyme contributes substantially to metabolism of approximately 50% of currently marketed drugs that undergo oxidative metabolism. As a result, drug-drug interactions involving inhibitors of CYP3A-mediated metabolism can be of great clinical consequence. It is the position of the authors that, because of the factors responsible for the broad substrate specificity of CYP3A, discovery and development of compounds across a large and broad portfolio that are completely devoid of CYP3A metabolism is not feasible. Thus, it is important that scientifically valid approaches to the discovery and development of compounds metabolised by CYP3A be realised. The clinical relevance of CYP3A metabolism is dependent on a multitude of factors that include the degree of intestinal and hepatic CYP3A-mediated first-pass extraction, the therapeutic index of the compound and the adverse event associated with inhibition of CYP3A metabolism. Thus, a better understanding of the disposition of a CYP3A-metabolised compound relative to the projected or observed therapeutic index (or safety margin) can provide ample evidence to support the continued development of a CYP3A substrate. This document will highlight current practices as well as the benefits and risks associated with those practices.


Asunto(s)
Hidrocarburo de Aril Hidroxilasas/metabolismo , Oxidorreductasas N-Desmetilantes/metabolismo , Especificidad por Sustrato/fisiología , Biotransformación/efectos de los fármacos , Biotransformación/fisiología , Fenómenos Químicos , Química Física , Citocromo P-450 CYP3A , Diseño de Fármacos , Humanos , Medición de Riesgo/métodos , Especificidad por Sustrato/efectos de los fármacos
10.
Curr Top Med Chem ; 11(4): 351-7, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21320064

RESUMEN

Quantitative human pharmacokinetic (PK) predictions play a critical role in assessing the quality of potential drug candidates and in selecting a human starting dose for clinical evaluation, where the parameters of clearance, volume of distribution, and bioavailability as well as the plasma concentration time profiles are the desired endpoints. While there are numerous reports validating the use of different methods for predictions, it still remains an open question as to what animal species to include when extrapolating the animal PK to human. Given toxicological assessment is generally conducted in two species, a rodent and a non-rodent species, prior to evaluation in human subjects, rat, dog and/or monkey are typically the species ADME scientists employ to evaluate PK. However, the question is, can we achieve an adequate prediction without the use of larger species such as monkey? In the end, the data and tools utilized for human PK predictions will depend on a number of factors such as information from observed human PK for structurally related compounds; the primary mechanism of clearance, and the availability of in silico and in vitro tools applicable to the respective clearance mechanism. Despite these dependencies, for most situations, adequate predictions can be achieved without the use of monkey PK for predicting human.


Asunto(s)
Diseño de Fármacos , Haplorrinos/metabolismo , Modelos Animales , Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Animales , Humanos , Tasa de Depuración Metabólica
11.
Clin Pharmacokinet ; 50(5): 331-47, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21456633

RESUMEN

BACKGROUND: The importance of predicting human pharmacokinetics during compound selection has been recognized in the pharmaceutical industry. To this end there are many different approaches that are applied. METHODS: In this study we compared the accuracy of physiologically based pharmacokinetic (PBPK) methodologies implemented in GastroPlus™ with the one-compartment approach routinely used at Pfizer for human pharmacokinetic plasma concentration-time profile prediction. Twenty-one Pfizer compounds were selected based on the availability of relevant preclinical and clinical data. Intravenous and oral human simulations were performed for each compound. To understand any mispredictions, simulations were also performed using the observed clearance (CL) value as input into the model. RESULTS: The simulation results using PBPK were shown to be superior to those obtained via traditional one-compartment analyses. In many cases, this difference was statistically significant. Specifically, the results showed that the PBPK approach was able to accurately predict passive distribution and absorption processes. Some issues and limitations remain with respect to the prediction of CL and active transport processes and these need to be improved to further increase the utility of PBPK modelling. A particular advantage of the PBPK approach is its ability to accurately predict the multiphasic shape of the pharmacokinetic profiles for many of the compounds tested. CONCLUSION: The results from this evaluation demonstrate the utility of PBPK methodology for the prediction of human pharmacokinetics. This methodology can be applied at different stages to enhance the understanding of the compounds in a particular chemical series, guide experiments, aid candidate selection and inform clinical trial design.


Asunto(s)
Simulación por Computador , Modelos Biológicos , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Perros , Semivida , Humanos , Inyecciones Intravenosas , Tasa de Depuración Metabólica , Microsomas Hepáticos/metabolismo , Preparaciones Farmacéuticas/química , Ratas , Estudios Retrospectivos , Especificidad de la Especie
12.
J Med Chem ; 54(21): 7693-704, 2011 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-21936524

RESUMEN

An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.


Asunto(s)
Antagonistas de Andrógenos/síntesis química , Antineoplásicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Ciclobutanos/síntesis química , Pirazoles/síntesis química , Administración Oral , Antagonistas de Andrógenos/farmacocinética , Antagonistas de Andrógenos/farmacología , Andrógenos/síntesis química , Andrógenos/farmacocinética , Andrógenos/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular , Ciclobutanos/farmacocinética , Ciclobutanos/farmacología , Resistencia a Antineoplásicos , Ensayos Analíticos de Alto Rendimiento , Humanos , Ligandos , Masculino , Ratones , Ratones Desnudos , Modelos Moleculares , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Pirazoles/farmacocinética , Pirazoles/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Mol Cancer Ther ; 9(6): 1618-28, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20530712

RESUMEN

Aberrant regulation of Notch signaling has been implicated in tumorigenesis. Proteolytic release of the Notch intracellular domain (NICD) by gamma-secretase plays a key role in Notch-dependent nuclear signaling. gamma-Secretase is an attractive pharmaceutical target for therapeutic intervention in cancer. We describe the potent antitumor effects of PF-03084014, a small molecule that is a reversible, noncompetitive, and selective gamma-secretase inhibitor. The ability of PF-03084014 to inhibit gamma-secretase activity was shown by the reduction of endogenous NICD levels and by the downregulation of Notch target genes Hes-1 and cMyc in the T-cell acute lymphoblastic leukemia (T-ALL) cell line HPB-ALL. PF-03084014 caused cell growth inhibition of several T-ALL cell lines via cell cycle arrest and induction of apoptosis. PF-03084014 treatment also resulted in robust NICD reduction in HBP-ALL xenograft models. Broad antitumor efficacy at well-tolerated dose levels was observed in six Notch-dependent models. Additional mechanism-of-action studies showed inhibition of tumor cell proliferation and induction of apoptosis in HPB-ALL tumors, suggesting that the antitumor activity of PF-03084014 may be mediated by its direct effects on tumor cell growth or survival. Further studies on PF-03084014-induced gastrointestinal toxicity identified an intermittent dosing schedule that displayed reduced body weight loss and sustained antitumor efficacy. We also showed that glucocorticoids abrogated PF-03084014-induced gastrointestinal toxicity and delayed administration of glucocorticoids did not compromise its protection effect. Collectively, the results show that inhibition of Notch signaling by PF-03084014 while minimizing gastrointestinal toxicity presents a promising approach for development of therapies for Notch receptor-dependent cancers. This compound is being investigated for the treatment of T-ALL and advanced solid tumors in phase I clinical trials.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Ensayos Clínicos como Asunto , Tracto Gastrointestinal/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/farmacología , Valina/análogos & derivados , Ensayos Antitumor por Modelo de Xenoinjerto , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos como Asunto/normas , Dexametasona/administración & dosificación , Dexametasona/farmacología , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Tracto Gastrointestinal/patología , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/toxicidad , Estructura Terciaria de Proteína , Receptores Notch/química , Receptores Notch/metabolismo , Tetrahidronaftalenos/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento , Valina/administración & dosificación , Valina/efectos adversos , Valina/farmacología
14.
Drug Metab Dispos ; 34(9): 1443-7, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16760229

RESUMEN

This study was designed to evaluate the use of cerebrospinal fluid (CSF) drug concentration and plasma unbound concentration (C(u,plasma)) to predict brain unbound concentration (C(u,brain)). The concentration-time profiles in CSF, plasma, and brain of seven model compounds were determined after subcutaneous administration in rats. The C(u,brain) was estimated from the product of total brain concentrations and unbound fractions, which were determined using brain tissue slice and brain homogenate methods. For theobromine, theophylline, caffeine, fluoxetine, and propranolol, which represent rapid brain penetration compounds with a simple diffusion mechanism, the ratios of the area under the curve of C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) were 0.27 to 1.5 and 0.29 to 2.1, respectively, using the brain slice method, and were 0.27 to 2.9 and 0.36 to 3.9, respectively, using the brain homogenate method. A P-glycoprotein substrate, CP-141938 (methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide), had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.57 and 0.066, using the brain slice method, and 1.1 and 0.13, using the brain homogenate method, respectively. The slow brain-penetrating compound, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl-]sarcosine, had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.94 and 0.12 using the brain slice method and 0.15 and 0.018 using the brain homogenate method, respectively. Therefore, for quick brain penetration with simple diffusion mechanism compounds, C(CSF) and C(u,plasma) represent C(u,brain) equally well; for efflux substrates or slow brain penetration compounds, C(CSF) appears to be equivalent to or more accurate than C(u,plasma) to represent C(u,brain). Thus, we hypothesize that C(CSF) is equivalent to or better than C(u,plasma) to predict C(u,brain). This hypothesis is supported by the literature data.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Fluoxetina/líquido cefalorraquídeo , Teobromina/líquido cefalorraquídeo , Teofilina/líquido cefalorraquídeo , Animales , Evaluación Preclínica de Medicamentos/métodos , Fluoxetina/sangre , Fluoxetina/farmacocinética , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Teobromina/sangre , Teobromina/farmacocinética , Teofilina/sangre , Teofilina/farmacocinética
15.
J Pharmacol Exp Ther ; 313(3): 1254-62, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15743928

RESUMEN

This study was designed 1) to examine the effects of blood-brain barrier (BBB) permeability [quantified as permeability-surface area product (PS)], unbound fraction in plasma (f(u,plasma)), and brain tissue (f(u,brain)) on the time to reach equilibrium between brain and plasma and 2) to investigate the drug discovery strategies to design and select compounds that can rapidly penetrate the BBB and distribute to the site of action. The pharmacokinetics of seven model compounds: caffeine, CP-141938 [methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide], fluoxetine, NFPS [N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine], propranolol, theobromine, and theophylline in rat brain and plasma after subcutaneous administration were studied. The in vivo log PS and log f(u,brain) calculated using a physiologically based pharmacokinetic model correlates with in situ log PS (R(2) = 0.83) and in vitro log f(u,brain) (R(2) = 0.69), where the in situ PS and in vitro f(u,brain) was determined using in situ brain perfusion and equilibrium dialysis using brain homogenate, respectively. The time to achieve brain equilibrium can be quantitated with a proposed parameter, intrinsic brain equilibrium half-life [t(1/2eq,in) = V(b)ln2/(PS . f(u,brain))], where V(b) is the physiological volume of brain. The in vivo log t(1/2eq,in) does not correlate with in situ log PS (R(2) < 0.01) but correlates inversely with log(PS . f(u,brain)) (R(2) = 0.85). The present study demonstrates that rapid brain equilibration requires a combination of high BBB permeability and low brain tissue binding. A high BBB permeability alone cannot guarantee a rapid equilibration. The strategy to select compounds with rapid brain equilibration in drug discovery should identify compounds with high BBB permeability and low nonspecific binding in brain tissue.


Asunto(s)
Proteínas Sanguíneas/metabolismo , Barrera Hematoencefálica , Encéfalo/metabolismo , Farmacocinética , Animales , Semivida , Masculino , Modelos Biológicos , Permeabilidad , Unión Proteica , Ratas , Ratas Sprague-Dawley , Factores de Tiempo
16.
Drug Metab Dispos ; 33(1): 165-74, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15502009

RESUMEN

Thirty-two structurally diverse drugs used for the treatment of various conditions of the central nervous system (CNS), along with two active metabolites, and eight non-CNS drugs were measured in brain, plasma, and cerebrospinal fluid in the P-glycoprotein (P-gp) knockout mouse model after subcutaneous administration, and the data were compared with corresponding data obtained in wild-type mice. Total brain-to-plasma (B/P) ratios for the CNS agents ranged from 0.060 to 24. Of the 34 CNS-active agents, only 7 demonstrated B/P area under the plasma concentration curve ratios between P-gp knockout and wild-type mice that did not differ significantly from unity. Most of the remaining drugs demonstrated 1.1- to 2.6-fold greater B/P ratios in P-gp knockout mice versus wild-type mice. Three, risperidone, its active metabolite 9-hydroxyrisperidone, and metoclopramide, showed marked differences in B/P ratios between knockout and wild-type mice (6.6- to 17-fold). Differences in B/P ratios and cerebrospinal fluid/plasma ratios between wild-type and knockout animals were correlated. Through the use of this model, it appears that most CNS-active agents demonstrate at least some P-gp-mediated transport that can affect brain concentrations. However, the impact for the majority of agents is probably minor. The example of risperidone illustrates that even good P-gp substrates can still be clinically useful CNS-active agents. However, for such agents, unbound plasma concentrations may need to be greater than values projected using receptor affinity data to achieve adequate receptor occupancy for effect.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Fármacos del Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/deficiencia , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/genética , Animales , Sistema Nervioso Central/efectos de los fármacos , Fármacos del Sistema Nervioso Central/administración & dosificación , Femenino , Ratones , Ratones Noqueados , Miembro 4 de la Subfamilia B de Casete de Unión a ATP
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